Supplementary,Tables!

Table&S1:!Asthma&seed&genes.!The!seed!genes!were!compiled!from!the!following!sources:!

Sources Genes References,(PubMed,ids) FCER1B,HLA>DRB1,HLA>DQB1,HLA> DPB1,STAT6,NR3C1,GFRA2,GATA2,SH2B3,IKZF2,GSTM1,GSTP1,GSTT1,FLG,IL10,IL18,CTLA Literature,)as)compiled)in)Vercelli)et)al)2008 4,HAVCR1,GPRA,NAT2,NOS1,CMA1,ACE,TBXA2R,CTA,SCGB1A1 18301422 CCL17,CCL22,CCL2,CD200,CX3CR1,CXCR1,CXCR2,IL8,CCL11,) Chemokines)pathway>Drug)target>genes CCL11,TNFRSF4,TNFSF4,ICOS,C5CHRNA3TRPA1TRPV1HRH4

Co>stim)pathways>Drug)target>genes TNFRSF4,TNFSF4,ICOS

Complement)pathways>Drug)target>genes C5 GPCR>ligand)inflammatory)mediators)>Drug)target> genes CHRNA3,TRPA1,TRPV1,HRH4,PTGDS,GPR44,HNMT,PTGER2

Growth)factors>Drug)target>genes F2RL1,FGF2,PDGFB

Inflammatory)signaling)>Drug)target>genes CSF2,IKBKB,NGF,PDE4,PIK3CA,STAT1,MAPK14,MAPK8,MMP12,SYK,IRAK3,OSM,TNFA

Leukotriene)pathway>Drug)target>genes ALOX5AP,LTB4R2,LTA4H,LTC4S,ALOX5,IFNB1,TLR7,TLR3,TLR9,TLR4

Pathogen)response)>Drug)target>genes IFNB1,TLR7,TLR3,TLR9,TLR4

Proteases>Drug)target>genes MMP9,TPSAB1,SPINK5,ELANE Structural)Genes/Mucosal)Epithelial)pathways)>Drug) target>genes CTNNA3,MUC7,TGFB1,CLCA1,MUC5AC

Th17>Drug)target>genes IL17,IL23A,IL6

Th2>Drug)target>genes IL13RA2,IL4,IL33,IL4R,IL9,IL25

Drug)target>genes ADORA2A,SRC,CD28,IL21,IL22,EGF,CD40

GWAS6Genes EDN1,GSDMA,GSDMB,HLA> 21103062,)20860503,) Asthma DQA1,IL18R1,IL2RB,MAVS,MYB,PDE11A,PDE4D,RAD50,RORA,SCG3,SLC22A5,SMAD3,VDR, 20622879,)20159242,) 20032318,19714205,211030 Childhood)Asthma CRB1,DENND1B,CHCHD9,TLE4,ADAM33,CCL5 62

Plasma)eosinophil)count IL1RL1,IL5,TSLP 19198610

YKL>40)levels CHI3L1 18403759 Table! S2:! Gene& expression& data.! Sources! of! the! differential! expression! gene! sets! used! for! the! bioinformatics!validation!of!the!DIAMOnD!module.!!

Differentially* & Data Name Title*of*study expressed* Analysis*type adj.p9value reference Year genes

!Asthma!exacerbatory!factors![Homo! Data!from! Am!J!Respir!Cell!Mol! !GSE470! AEF 111!genes 2003 & sapiens] paper Biol.!2008!,38:324L36

Data!from! Am!J!Respir!Cell!Mol! GSE473! PHL PGA!Human!CD4+!Lymphocytes 361!genes 2003 paper Biol.!2008!,38:324L36 &

Am!J!Respir!Cell!Mol! Effects!of!allergen!challenge!on! Data!from! GSE3004 ACA 63!genes p<0.01 Biol.!2008!,38:324L 2005 airway!epithelial!cell!gene!expression paper 36. & &

!Gene!expression!data!from!severe! p<0.05! asthmatic!children!!PBMC!profiles! Linear!models! (Benjamini!&! !GSE16032! SPAEC 135!genes! 2009 during!acute!exacerbation!versus! (Limma) Hochberg!(False! convalescence![Homo!sapiens] discovery!rate))

Decreased!fibronectin!production! significantly!contributes!to! Data!from! Am!J!Respir!Cell!Mol! GSE18965 FPSDR 1487!genes! 2010 dysregulated!repair!of!asthmatic! paper Biol.!2008!,38:324L36 epithelium

p<0.02! !Comparison!of!mRNA!expression!in! Linear!models! (Benjamini!&! !GSE31773! PSA circulating!TLcells!from!patients!with! 554!genes 2011 (Limma) Hochberg!(False! severe!asthma![Homo!sapiens] discovery!rate))

GenomeLWide!Profiling!of!Airway! Proc!Natl!Acad!Sci!U! data!from! GSE4302 GWPAE Epithelial!Cells!in!Asthmatics,! 187!genes S!A!2007,!104:15858L 2007 paper Smokers!and!Healthy!Controls 63 GSE23611!

p<0.02! 1580! !isolated!alveolar!macrophages! Linear!models! (Benjamini!&! !GSE2125! IAM (smokers)/1998 2003 [Homo!sapiens] (Limma) Hochberg!(False! (Nonsmokers) discovery!rate))

Data!from! Am!J!Respir!Cell!Mol! CSPC CSPC 452!genes p<0.05 2000 paper Biol.!2008!,38:324L36 Table& S3:, Asthma;specific& pathways.! ThirtyAfive! asthma! related! pathways! identified! by! the! GeneGO! MetaACore!software!and!their!total!number!of!genes.&

GeneGo%pathways Number%of%genes IFN$gamma(and(Th2(cytokines$induced(inflammatory(signaling(in(normal(and(asthmatic( airway(epithelium 173 IL$17(and(IL$17F$induced(inflammatory(signaling(in(normal(and(asthmatic(airway(epithelium 120 Interleukins$induced(inflammatory(signaling(in(normal(and(asthmatic(airway(epithelium 136 Lysophospholipid(mediators$induced(inflammatory(signaling(in(normal(and(asthmatic( airway(epithelium 533 Proteases(and(EGFR$induced(mucin(synthesis(in(normal(and(asthmatic(epithelium 345 TNF$alpha$induced(inflammatory(signaling(in(normal(and(asthmatic(airway(epithelium 259 Hypertrophy(of(asthmatic(airway(smooth(muscle(cells 238 TGF$beta(1$mediated(induction(of(EMT(in(normal(and(asthmatic(airway(epithelium 245 Probable(BMP4$mediated(induction(of(EMT(in(airway(epithelium 113 Disruption(of(apoptosis,(proliferation(and(shedding(of(epithelial(cells(in(asthma 317 Disruption(of(epithelial(layer(restitution(in(asthma 171 Induction(of(mucin(secretion(in(airway(goblet(cells(by(purinergic(receptors 342 Inflammatory(factors$induced(expression(of(mucins(in(normal(and(asthmatic(epithelium 210 Prostaglandins(and(leukotrienes$mediated(induction(of(expression(of(mucins(in(normal(and( asthmatic(epithelium 225 Retinoic(acid(maintains(mucocilliary(differentiation(and(mucins(expression(in(normal(and( asthmatic(airway(epithelium 141 Th2$cytokines$induced(expression(of(mucins(in(asthma 194 Th2$cytokines$induced(mucous(metaplasia(in(asthma 165 MAPK$mediated(proliferation(of(normal(and(asthmatic(smooth(muscle(cells 247 MAPK$independent(pathway(of(regulation(proliferation(of(normal(and(asthmatic(smooth( muscle(cells 333 Extracellular(matrix$regulated(proliferation(of(airway(smooth(muscle(cells(in(asthma 179 Cytokine(production(by(Th17(cells 199 Immune(response_Th1(and(Th2(cell(differentiation 213 Immune(response_IL$17(signaling(pathways 350 Immune(response_PGE2(signaling(in(immune(response 196 Immune(response_NF$AT(signaling(and(leukocyte(interactions 337 Immune(response_Histamine(signaling(in(dendritic(cells 288 Immune(response_TREM1(signaling(pathway 330 Immune(response_MIF(in(innate(immunity(response 204 Development_Regulation(of(epithelial$to$mesenchymal(transition((EMT) 318 Immune(response_Histamine(H1(receptor(signaling(in(immune(response 281 Normal(and(pathological(TGF$beta$mediated(regulation(of(cell(proliferation 158 Immune(response(_CCR3(signaling(in(eosinophils 381 Immune(response_IL$15(signaling 351 Immune(response_IL$13(signaling(via(JAK$STAT 132 Immune(response_IL$4(signaling(pathway 319 Table& S4:! Comorbidity& analysis.! List! of! all! diseases! with! increased! comorbidity! with! asthma! and! the! number! of! their! associated! genes.! The! pAvalue! (Fisher’s! exact! test)! gives! the! enrichment! of! the! 350! DIAMOnD!genes!with!the!diseaseAassociated!genes!!

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number(of(all( Number(of( RR RR disease(genes(in( found(genes(in( RR lowerbound upperbound Comorbid(disease(to(asthma( interactome( 350( P9value(

Disorders(involving(the(immune(mechanism( 45( 7( 3.50E:04( 2.141628613( 1.48225894( 3.094313005(

Congenital(anomalies(of(the(integument,(Ichthyosis(congenita( 71( 6( 2.00E:02( 2.181108365( 1.451405504( 3.277673736(

Diseases(of(white(blood(cells( 20( 4( 2.70E:03( 1.951404493( 1.383086505( 2.753247522(

Disorders(of(lipoid(metabolism,(Lipodystrophy( 5( 3( 2.60E:04( 2.137210606( 1.218197912( 3.749529639(

Other(endocrine(disorders( 10( 3( 2.80E:03( 1.551643308( 1.290869394( 1.865097249( Disorders(involving(the(immune(mechanism,(Combined(immunity( deficiency( 17( 3( 1.30E:02( 2.759940969( 1.386447374( 5.494095412(

Overweight,(obesity(and(other(hyperalimentation( 26( 3( 4.20E:02( 2.119876087( 2.084896512( 2.155442535(

Cardiomyopathy,(Other(primary(cardiomyopathies( 31( 2( 2.40E:01( 1.620611052( 1.589758166( 1.652062709(

Cardiomyopathy( 32( 2( 2.50E:01( 1.607315797( 1.578103608( 1.637068732(

Chronic(airway(obstruction,(not(elsewhere(classified( 1( 1( 3.00E:02( 2.422866403( 2.407641126( 2.438187961(

Contact(dermatitis(and(other(eczema( 1( 1( 3.00E:02( 1.646203094( 1.564449407( 1.732228998(

Diseases(of(white(blood(cells,(Eosinophilia( 1( 1( 3.00E:02( 4.554252927( 4.213928913( 4.922062083( Disorders(involving(the(immune(mechanism,( Hypogammaglobulinemia,(unspecified( 1( 1( 3.00E:02( 4.19521066( 3.647478974( 4.825193678(

Poisoning(by(water,(mineral,(and(uric(acid(metabolism(drugs( 1( 1( 3.00E:02( 8.095143306( 7.62108895( 8.59868525( Strabismus(and(other(disorders(of(binocular(eye(movements,(Other( and(unspecified(heterotropia( 1( 1( 3.00E:02( 2.013630401( 1.035432541( 3.915955149( Other(diseases(of(lung,(Other(diseases(of(lung,(not(elsewhere( classified( 2( 1( 5.90E:02( 2.589269223( 2.519419893( 2.661055081(

Other(disorders(of(thyroid,(Other(specified(disorders(of(thyroid( 2( 1( 5.90E:02( 1.631167268( 1.246986997( 2.133708421(

Other(diseases(of(lung( 3( 1( 8.70E:02( 2.589269223( 2.519419893( 2.661055081(

Anxiety,(dissociative(and(somatoform(disorders( 4( 1( 1.10E:01( 2.331397137( 2.297720548( 2.365567308( Diseases(of(white(blood(cells,(Functional(disorders(of( polymorphonuclear(neutrophils( 4( 1( 1.10E:01( 1.951404493( 1.383086505( 2.753247522(

Lipoma,(Lipoma,(unspecified(site( 4( 1( 1.10E:01( 1.67355976( 1.193282974( 2.34714006(

Migraine,(Migraine,(unspecified( 4( 1( 1.10E:01( 1.667642309( 1.546868517( 1.797845675( Other(disorders(of(bone(and(cartilage,(Other(and(unspecified( disorders(of(bone(and(cartilage( 4( 1( 1.10E:01( 1.884875851( 1.818875248( 1.953271383(

Migraine( 5( 1( 1.40E:01( 1.667642309( 1.546868517( 1.797845675(

Postinflammatory(pulmonary(fibrosis( 6( 1( 1.70E:01( 2.229826227( 2.184015365( 2.276597995(

Disorders(of(tooth(development(and(eruption( 10( 1( 2.60E:01( 1.652392976( 1.203388861( 2.268927888(

Other(disorders(of(bone(and(cartilage( 16( 1( 3.90E:01( 2.110697713( 1.561304027( 2.853412761( Table,S6:,GWAS,analysis.,DIAMOnD!genes!with!pAvalues!

Gene SNP_GABRIEL P.value SNP_EVE P.value2 IL5 rs2069812 0.0035 rs736801 0.0015 IL4R rs1805012 0.00058 rs2107357 0.0045 CD200 rs4682103 0.000086 rs2895395 0.0046 HLA5G rs2517826 0.01 rs3900925 0.0012 ICOS rs11571312 0.00068 rs2081725 0.0013 HLA5DRB1 rs3129763 2.28E505 rs2516049 0.0038 BCL2 rs2849382 0.0042 rs4987768 0.00061 PLA2G4A rs6665890 0.01 rs642508 0.0013 RARA rs2715556 0.002 rs2715553 0.0033 PPARA rs11090910 0.01 rs6008197 0.0001 IRS2 rs12584136 0.0091 rs9515116 0.001 IRF1 rs12521868 6.29E507 rs13164856 0.00025 PAK1 rs7109180 0.00025 rs10899379 0.01 SMAD4 s7244227 0.012 rs17663887 0.025 TOP2A rs2715556 0.0028 rs2715553 0.0033 CIITA rs17229044 0.0003 rs3743976 0.002 CAMK2A rs1432833 0.00042 rs4704525 0.0025 RET rs752978 0.015 rs2251674 0.0018 DOK1 rs759075 0.0013 rs10210396 0.24 Table& S8:! Enrichment! of! steroid! response! genes! (differentially! expressed)! in! asthma! disease! module! exclusive!of!GCR!pathway!genes.!!

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, Total$DE$$ Outside$ DIAMOnD$ Data$set genes In$Module Module p4value genes p4value4D , Normal'DE'genes 628 47 424 7.64E409 37 5.06E408 Asthma'DE'genes 562 42 377 4.40E408 33 2.65E407 ,

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Table&S9:!Twenty!pathways!with!the!highest!enrichment!with!genes!found!to!be!differentially!expressed! in!normal!and!asthmatic!fibroblast!cells!under!glucocorticoid!treatment.! Column!1!gives!the!pathway! and!the!contained!differentially!expressed!genes,!columns!2!and!3!the!raw!pAvalue!and!foldAchange!of! the!differential!expression!analysis!and!column!4!the!pathway!enrichment!pAvalue!(Fisher’s!exact!test).!

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! &

! , Disease GSE)id ID adj.P.Val P.Value t B logFC Gene.symbol crohn's GSE3365 207112_s_at 1.70E601 7.67E602 61.788299 65.074263 60.3484484 GAB1 Hashimoto Grave's ! Celiac CGSE11501 ILMN_17816720.91559 6.68E601 60.430133 66.08368 60.0081987 GAB1 AnkylosingCspondylitis GSE25101 ! MultipleCSclerosis GSE21942 226002_at 1.09E603 5.15E605 64.76 1.81 63.84E601 GAB1 Psoriasis GSE14905 229114_at 5.92E606 5.16E607 65.71 5.80187 67.30E601 GAB1 RheumatoidCArthritis GSE2053 15704 0.98317 9.13E601 60.1137671 66.0394 60.0865509 GAB1 ! SystemicCLupusCErythematosus GSE46923 214987_at 0.3899 5.30E602 62.2080186 64.1683 60.6638811 GAB1 TypeC1CDiabetes GSE17635 GI_45038506S0.619878 4.36E601 0.793898 65.8525 0.12736474 GAB1 UlcerativeCColitis GSE3365 214987_at 1.04E601 2.38E602 2.310773 63.91248 0.5716394 GAB1

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Table&S10:!Case!vs!control!differential!expression!analysis!using!Gene!Expression!Omnibus!(GEO)!data! set.!Differential!expression!analysis!was!done!using!the!limma!package!in!Bioconductor.!We!find!GAB1! not!differentially!expressed!in!most!of!the!inflammatoryArelated!diseases.!!

We! also! check! the! GAB1! differentially! expressed! status! in! DiseaseAconnect! data! that! include! 996! datasets!with!4,273!subsets!and!20,915!samples.!Differentially!expressed!genes!are!defined!as!genes! with!tAtest!PAvalues!

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